The health significance of the research proposed in this application derives from the new organic synthesis methodology to be developed. It is our aim to provide versatile new organic synthesis tools to enable the future development of new chemical agents for treating cardiovascular disease. The synthesis targets of our HL program are agents that display biological activity relevant to cardiovascular therapy. Particularly in the areas where our synthetic chemistry is well-developed (e.g. the pumiliotoxin A alkaloid area) significant health relevance derives from the use of synthesis to refine current models of the molecular level basis of the cardiovascular activity. Both exploratory and total synthesis investigations will be pursued. In the pumiliotoxin A alkaloid area this chemistry is sufficiently developed that total synthesis can be now effectively utilized to study the molecular level basis for cardiotonic activity in this series. In addition to the pumiliotoxin A alkaloids four structurally diverse natural product families are targeted for extensive synthesis investigation during the upcoming HL project period: the heteroyohimbine alkaloids (-)-ajmalicine and (+)-19-epiajmalicine, aloperine, sarain A and gelsemine. These targets are chosen because of their therapeutic potential for treating cardiovascular diseases and because of the need for better synthetic access to molecules exemplified by these structural types. The major chemical thrust of this application is to exploit discoveries made during the current project period concerning the pivotal role that external or internal heteroatom nucleophiles can play in Mannich cyclization reactions. The overall aim is to develop versatile methods for preparing nitrogen heterocycles that utilize simple alkynes or alkenes as components in Mannich cyclization reactions. The designed involvement of a heteroatom nucleophile obviates the need for more complex, expensive, labile, and environmentally hazardous heterofunctionalized pi-nucleophiles such as vinyl-, allyl-, or propargylsilanes (or stannanes).